Method for synthesis of 8-alkoxy-9H-isothiazolo[5,4-B]quinoline-3,4-diones

ABSTRACT

The present invention provides process for synthesis of 8-methoxy-9H-isothiazolo[5,4-b]quinoline-3,4-diones and 8A,9-dihydro-4aH-isothiazolo[5,4-b]quinoline-3,4-diones of the Formula A. 
                         
The substituents R, R 5 , R 6 , R 7 , R 8  and R 9  are defined herein. The invention also provides novel synthetic intermediates useful in the synthesis of 8-methoxy-9H-isothiazolo[5,4-b]quinoline-3,4-diones and 8A,9-dihydro-4 a H-isothiazolo[5,4-b]quinoline-3,4-diones.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. Provisional Application No.60/822,582 filed Jul. 16, 2006, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention provides methods for synthesis of8-alkoxy-9H-isothiazolo[5,4-b]quinoline-3,4-diones and8A,9-dihydro-4aH-isothiazolo[5,4-b]quinoline-3,4-diones. The inventionalso provides synthetic intermediates useful in the synthesis of8-alkoxy-9H-isothiazolo[5,4-b]quinoline-3,4-diones and8A,9-dihydro-4aH-isothiazolo[5,4-b]quinoline-3,4-diones.

BACKGROUND OF THE INVENTION

Structural Formula A, shown below, and its tautomers represented byFormula B represent a class of potent antimicrobial compounds. WithinFormula A and B the variables, e.g. R, R₃, and R₅ to R₉ carry thedefinitions that follow.

R is hydrogen, or R is C₁-C₆alkyl, C₂-C₆alkenyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (aryl)C₀-C₄alkyl, or(C₂-C₆heterocycloalkyl)C₀-C₂alkyl, each of which is substituted with 0to 5 substituents independently chosen from halogen, hydroxy, amino,cyano, nitro, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,mono- and di-C₁-C₄alkylamino, C₂-C₄alkanoyl, and C₁-C₄alkylthio.

R₃ is hydrogen, C₁-C₆alkyl, or C₂-C₆alkanoyl.

R₅ is hydrogen, hydroxy, amino, C₁-C₂alkyl, C₁-C₂alkoxy, mono- ordi-(C₁-C₄alkyl)amino, or mono-, di-, or tri-C₁-C₄alkylhydrazinyl.

R₆ is hydrogen, halogen, or amino.

R₇ is bromo or R₇ is a nitrogen-linked C₁-C₄alkylamino substituted witha 5 or 6-membered heteroaryl group having 1 or 2 heteroatomsindependently chosen from N, O, and S, or substituted with aheterocycloalkyl group, which has 4 to 8 ring members, including 1 or 2ring heteroatoms independently chosen from N, O, and S.

R₇ is a nitrogen-linked heterocycloalkyl or heterocycloalkenyl group,each of which has 4 to 8 ring members, including 0, 1, or 2 additionalring heteroatoms independently chosen from N, O, and S, forming part ofa bicyclic system with a 3- to 8-membered cycloalkyl or heterocycloalkylring in fused or spiro orientation.

R₇ is a nitrogen-linked 6-membered heterocycloalkyl group, 0, 1, or 2additional ring heteroatoms independently chosen from N, O, and S, andbridged with a methylene or ethylene bridge.

R₇ is a group of the formula

optionally attached to a C₃-C₇ spiro cycloalkyl or a spiroheterocycloalkyl.

R_(A) is hydrogen, or R_(A) is C₁-C₈alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₂-C₆alkanoyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,(C₄-C₇cycloalkenyl)C₀-C₄alkyl, (aryl)C₀-C₄alkyl, (aryl)(C═O)—, or(C₂-C₆heterocycloalkyl)C₀-C₄alkyl, each of which is substituted with 0to 5 substituents independently chosen from halogen, hydroxy, amino,cyano, nitro, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,mono- and di-C₁-C₄alkylamino, C₂-C₄alkanoyl, and C₁-C₄alkylthio.

R_(B) is hydrogen or C₁-C₄alkyl.

Each of which R₇ is substituted with 0 or 1 or more substituentsindependently chosen from (a) and 0, 1, or 2 substituents chosen from(b); wherein (a) is chosen from halogen, hydroxy, amino, nitro,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, and (b) isoxo, cyano, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl, C₁-C₆alkylthio,C₂-C₆alkanoyl, (mono- or di-C₁-C₄alkyl)aminoC₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (C₃-C₇cycloalkyl)aminoC₀-C₄alkyl,(C₃-C₇cycloalkyl)(C₁-C₄alkyl)aminoC₀-C₄alkyl,(heterocycloalkyl)C₀-C₄alkyl, (5-membered heteroaryl)C₀-C₄alkyl, or(aryl)C₀-C₄alkyl, where each of (b) other than oxo and cyano issubstituted with 0 to 2 substituents independently chosen from halogen,hydroxy, amino, cyano, nitro, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy.

R₈ is C₁-C₆alkyl, C₁-C₂haloalkyl, or C₃-C₇cycloalkyl substituted with 0or 1 or more halogen atoms.

R₉ is C₁-C₄alkyl, cyclopropyl, or phenyl, each of which is substitutedwith 0 to 3 substituents independently chosen from halogen, hydroxy,amino, C₁-C₂alkyl, C₁-C₂alkoxy, mono- and di-(C₁-C₂)alkylamino,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

The synthesis of these compounds has been described previously, in U.S.provisional patent application Ser. No. 11/494,205, filed Jul. 27, 2006,which is hereby incorporated by reference at pages 58 to 76, for itsteachings regarding the synthesis of8-alkoxy-9H-isothiazolo[5,4-b]quinoline-3,4-diones and in U.S. patentapplication Ser. No. 11/271,556 filed Nov. 10, 2005 which is herebyincorporated by reference at pages 43 to 51, for its teachings regardingthe synthesis of8A,9-dihydro-4aH-isothiazolo[5,4-b]quinoline-3,4-diones.

The previously described synthetic method produces significant amountsof impurities. Additionally the synthesis must be carried out, in part,in DMSO, a reactive and high-boiling solvent. The previously reportedmethod requires chromatographic purification of an intermediate, whilethe procedure reported here does not require chromatographicpurification. Additionally the previously reported method utilizesm-CPBA, a potentially explosive oxidant. Thus, a convenient andefficient synthesis that provides8-alkoxy-9H-isothiazolo[5,4-b]quinoline-3,4-diones and8A,9-dihydro-4aH-isothiazolo[5,4-b]quinoline-3,4-diones with reducedproduction of impurities and side products, and avoids the use of DMSOand m-CPBA is desirable. The present invention fulfills this need andprovides additional advantages, which are described herein.

SUMMARY OF THE INVENTION

The present invention provides a process for making8-alkoxy-9H-isothiazolo[5,4-b]quinoline-3,4-diones and8A,9-dihydro-4aH-isothiazolo[5,4-b]quinoline-3,4-diones.

Thus in a first aspect the invention provides a method of making an8-alkoxy-9H-isothiazolo[5,4-b]quinoline-3,4-dione, which method includesoxidizing a compound of Formula I with an oxidizing agent to make asulfone compound of Formula II. Within Formula I and II X is fluoro,bromo, or chloro and R₂ and R₄ are independently chosen from C₁-C₆alkyl,C₂-C₆alkenyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl, (aryl)C₀-C₄alkyl, and(C₂-C₆heterocycloalkyl)C₀-C₂alkyl, each of which is substituted with 0to 5 substituents independently chosen from halogen, hydroxy, amino,cyano, nitro, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,mono- and di-C₁-C₄alkylamino, C₂-C₄alkanoyl, and C₁-C₄alkylthio. WithinFormula I R₁₀ is —SH or —SR₄.

The method also includes reacting a sulfone compound of Formula II witha cyclic secondary amine to form a compound of Formula III, in which R₇represents an N-linked heterocycloalkyl substituent. The product of thisstep is then converted to a thiol compound with a conversion reagent.

The method includes cyclization of a compound of Formula IV to make an8-alkoxy-9H-isothiazolo[5,4-b]quinoline-3,4-dione or8A,9-dihydro-4aH-isothiazolo[5,4-b]quinoline-3,4-diones of Formula A.The cyclization may be effected by reacting a thiol compound of formulaIV with hydroxylamine-O-sulfonic acid.

The present invention provides synthetic intermediates useful for making8-alkoxy-9H-isothiazolo[5,4-b]quinoline-3,4-diones and8A,9-dihydro-4aH-isothiazolo[5,4-b]quinoline-3,4-diones. For example theinvention provides synthetic intermediates of Formula I-Formula IV.

Within Formula I-Formula IV the variables X, R₂, R₄, R₅, R₆, R₇, R₈, andR₉ carry the definitions that follow.

X is chloro, bromo, fluoro; iodo, or triflate.

R₂ is C₁-C₆alkyl, C₂-C₆alkenyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,(aryl)C₀-C₄alkyl, or (C₂-C₆heterocycloalkyl)C₀-C₂alkyl, each of which issubstituted with 0 to 5 substituents independently chosen from halogen,hydroxy, amino, cyano, nitro, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, mono- and di-C₁-C₄alkylamino, C₂-C₄alkanoyl, andC₁-C₄alkylthio.

R₄ is C₁-C₆alkyl, C₂-C₆alkenyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,(aryl)C₀-C₄alkyl, or (C₂-C₆heterocycloalkyl)C₀-C₂alkyl, each of which issubstituted with 0 to 5 substituents independently chosen from halogen,hydroxy, amino, cyano, nitro, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, mono- and di-C₁-C₄alkylamino, C₂-C₄alkanoyl, andC₁-C₄alkylthio.

R₅ is hydrogen, hydroxy, amino, C₁-C₂alkyl, C₁-C₂alkoxy, mono- ordi-(C₁-C₄alkyl)amino, or mono- or di-C₁-C₄alkylhydrazinyl.

R₆ is hydrogen, halogen, or amino.

R₇ is a nitrogen-linked heterocycloalkyl group, which has 4 to 8 ringmembers, including 0, 1, or 2 additional ring heteroatoms independentlychosen from N, O, and S.

Or, R₇ is a nitrogen-linked C₁-C₄alkylamino substituted with a 5 or6-membered heteroaryl group having 1 or 2 heteroatoms independentlychosen from N, O, and S, or substituted with a heterocycloalkyl group,which has 4 to 8 ring members, including 1 or 2 ring heteroatomsindependently chosen from N, O, and S.

Or, R₇ is a nitrogen-linked heterocycloalkyl or heterocycloalkenylgroup, each of which has 4 to 8 ring members, including 0, 1, or 2additional ring heteroatoms independently chosen from N, O, and S,forming part of a bicyclic system with a 3- to 8-membered cycloalkyl orheterocycloalkyl ring in fused or spiro orientation,

Or, R₇ is a nitrogen-linked 6-membered heterocycloalkyl group, having 0,1, or 2 additional ring heteroatoms independently chosen from N, O, andS, and bridged with a methylene or ethylene bridge.

Or, R₇ is a group of the formula

optionally attached to a C₃-C₇ spiro cycloalkyl or a spiroheterocycloalkyl.

R_(A) is hydrogen, or R_(A) is C₁-C₈alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₂-C₆alkanoyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,(C₄-C₇cycloalkenyl)C₀-C₄alkyl, (aryl)C₀-C₄alkyl, (aryl)(C═O)—, or(C₂-C₆heterocycloalkyl)C₀-C₄alkyl, each of which is substituted with 0to 5 substituents independently chosen from halogen, hydroxy, amino,cyano, nitro, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,mono- and di-C₁-C₄alkylamino, C₂-C₄alkanoyl, and C₁-C₄alkylthio.

R_(B) is hydrogen or C₁-C₄alkyl.

Each of which R₇ is substituted with 0 or 1 or more substituentsindependently chosen from (a) and 0, 1, or 2 substituents chosen from(b); wherein (a) is chosen from halogen, hydroxy, amino, nitro,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, and (b) isoxo, cyano, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl, C₁-C₆alkylthio,C₂-C₆alkanoyl, (mono- or di-C₁-C₄alkyl)aminoC₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (C₃-C₇cycloalkyl)aminoC₀-C₄alkyl,(C₃-C₇cycloalkyl)(C₁-C₄alkyl)aminoC₀-C₄alkyl,(heterocycloalkyl)C₀-C₄alkyl, (5-membered heteroaryl)C₀-C₄alkyl, or(aryl)C₀-C₄alkyl, where each of (b) other than oxo and cyano issubstituted with 0 to 2 substituents independently chosen from halogen,hydroxy, amino, cyano, nitro, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy.

R₈ is C₁-C₆alkyl, C₁-C₂haloalkyl, or C₃-C₇cycloalkyl substituted with 0or 1 or more halogen atoms.

R₉ is C₁-C₄alkyl, cyclopropyl, or phenyl, each of which is substitutedwith 0 to 3 substituents independently chosen from halogen, hydroxy,amino, C₁-C₂alkyl, C₁-C₂alkoxy, mono- and di-(C₁-C₂)alkylamino,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

DETAILED DESCRIPTION OF THE INVENTION

Chemical Description and Terminology

Prior to setting forth the invention in detail, it may be helpful toprovide definitions of certain terms to be used herein. Compounds of thepresent invention are generally described using standard nomenclature.

In certain situations, the compounds described and claimed herein maycontain one or more asymmetric elements such as stereogenic centers,stereogenic axes and the like, e.g. asymmetric carbon atoms, so that thecompounds can exist in different stereoisomeric forms. These compoundscan be, for example, racemates or optically active forms. For compoundswith two or more asymmetric elements, these compounds can additionallybe mixtures of diastereomers. For compounds having asymmetric centers,it should be understood that all of the optical isomers and mixturesthereof are encompassed. In addition, compounds with carbon-carbondouble bonds may occur in Z- and E-forms, with all isomeric forms of thecompounds being included in the present invention. In these situations,the single enantiomers, i.e., optically active forms can be obtained byasymmetric synthesis, synthesis from optically pure precursors, or byresolution of the racemates. Resolution of the racemates can also beaccomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral HPLC column.

Where a compound exists in various tautomeric forms, the invention isnot limited to any one of the specific tautomers, but rather includesall tautomeric forms.

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample, and without limitation, isotopes of hydrogen include tritiumand deuterium and isotopes of carbon include ¹¹C, ¹³C, and ¹⁴C.

Certain compounds are described herein using a general formula thatincludes variables, e.g. R, R₁ to R₉, and X. Unless otherwise specified,each variable within such a formula is defined independently of othervariables. Thus, if a group is said to be substituted, e.g. with 0-2 R*,then said group may be substituted with up to two R* groups and R* ateach occurrence is selected independently from the definition of R*.

The term “substituted,” as used herein, means that any one or morehydrogen atoms on the designated atom or group is replaced with aselection from the indicated group, provided that the designated atom'snormal valence is not exceeded. When a group is substituted by an “oxo”substituent a carbonyl bond replaces two hydrogen atoms on a carbon. An“oxo” substituent on an aromatic group or heteroaromatic group destroysthe aromatic character of that group, e.g. a pyridyl substituted withoxo is a pyridone. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds oruseful synthetic intermediates. A stable compound or stable structure ismeant to imply a compound that is sufficiently robust to surviveisolation from a reaction mixture, and subsequent formulation into aneffective therapeutic agent. Unless otherwise specified substituents arenamed into the core structure. For example, it is to be understood thatwhen (cycloalkyl)alkyl is listed as a possible substituent the point ofattachment of this substituent to the core structure is in the alkylportion.

The exception to naming substituents into the ring is when thesubstituent is listed with a dash (“—”) or double bond (“═”) that is notbetween two letters or symbols. In that case the dash or double bondsymbol is used to indicate a point of attachment for a substituent. Forexample, —CONH₂ is attached through the carbon atom.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, having thespecified number of carbon atoms. Thus, the term C₁-C₄ alkyl as usedherein includes alkyl groups having from 1 to about 4 carbon atoms. WhenC₀-C_(n) alkyl is used herein in conjunction with another group, forexample, (aryl)C₀-C₄ alkyl, the indicated group, in this case aryl, iseither directly bound by a single covalent bond (C₀), or attached by analkyl chain having the specified number of carbon atoms, in this casefrom 1 to about 4 carbon atoms. Examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl,n-pentyl, and sec-pentyl.

“Alkoxy” represents an alkyl group as defined above with the indicatednumber of carbon atoms attached through an oxygen bridge. Examples ofalkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy,i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy,3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and3-methylpentoxy. An “(alkoxy)alkyl group is an alkoxy group as definedherein attached through its oxygen atom to an alkyl bridge where thepoint of attachment to the substituted group is in the alkyl group.

“Alkanoyl” indicates an alkyl group as defined above, attached through aketo (—(C═O)—) bridge. Alkanoyl groups have the indicated number ofcarbon atoms, with the carbon of the keto group being included in thenumbered carbon atoms. For example a C₂alkanoyl group is an acetyl grouphaving the formula CH₃(C═O)—.

As used herein, “mono- and/or di-alkylamino” indicate secondary ortertiary alkyl amino groups, wherein the alkyl groups are as definedabove and have the indicated number of carbon atoms. The point ofattachment of the alkylamino group is on the nitrogen. Examples of mono-and di-alkylamino groups include ethylamino, dimethylamino, andmethyl-propyl-amino. “mono- and/or di-(alkyl)aminoalkyl indicates amono- and di-(alkyl)amino substituents as described herein attached tothe group it substituted via a covalently bound alkyl linker having theindicated number of carbon atoms.

The term “mono-, di-, or tri-alkylhydrazinyl” indicates from 1 to 3independently chosen alkyl groups as defined above attached through asingle-bonded nitrogen-nitrogen linkage. At least one of the alkylgroups is attached to the terminal nitrogen (the nitrogen not bound tothe core structure). When the term mono- or di-alkylhydrazinyl is usedonly the terminal nitrogen is alkyl substituted. Examples ofalkylhydrazinyl groups include 2-butyl-1-hydrazinyl,2-butyl-2-methyl-1-hydrazinyl, and 1,2-dimethyl-2-propyl-1-hydrazinyl.

The term “alkylthio” indicates an alkyl group as defined above attachedthrough a sulfur linkage, i.e. a group of the formula alkyl-S—. Examplesinclude ethylthio and pentylthio.

As used herein, the term “aminoalkyl” indicates an alkyl group asdefined above substituted with at least one amino substituent.Similarly, the term “hydroxyalkyl” indicates an alkyl group as definedabove, substituted with at least one hydroxyl substituent. In certaininstances the alkyl group of the aminoalkyl or hydroxyalkyl group may befurther substituted.

As used herein, the term “aryl” indicates aromatic groups containingonly carbon in the aromatic ring or rings. Typical aryl groups contain 1to 3 separate, fused, or pendant rings and from 6 to about 18 ringatoms, without heteroatoms as ring members. When indicated, such arylgroups may be further substituted with carbon or non-carbon atoms orgroups. Such substitution may include fusion to a 5 to 7-memberedsaturated cyclic group that optionally contains 1 or 2 heteroatomsindependently chosen from N, O, and S, to form, for example, a3,4-methylenedioxy-phenyl group. Aryl groups include, for example,phenyl, naphthyl, including 1-naphthyl and 2-naphthyl, and bi-phenyl.

In the term “(aryl)alkyl”, aryl and alkyl are as defined above, and thepoint of attachment is on the alkyl group. This term encompasses, but isnot limited to, benzyl, phenylethyl, and piperonyl.

“Cycloalkyl” as used herein, indicates a saturated hydrocarbon ringgroup, having only carbon ring atoms and having the specified number ofcarbon atoms, usually from 3 to about 8 ring carbon atoms, or from 3 toabout 7 carbon atoms. Examples of cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl as well as bridged or cagedsaturated ring groups such as norborane or adamantane. In the term“(cycloalkyl)alkyl” the terms cycloalkyl, and alkyl are as definedabove, and the point of attachment is on the alkyl. These terms includeexamples such as cyclopropylmethyl and cyclohexylmethyl.

“Haloalkyl” indicates both branched and straight-chain saturatedaliphatic hydrocarbon groups having the specified number of carbonatoms, substituted with 1 or more halogen atoms, generally up to themaximum allowable number of halogen atoms. Examples of haloalkylinclude, but are not limited to, trifluoromethyl, difluoromethyl,2-fluoroethyl, and penta-fluoroethyl.

“Haloalkoxy” indicates a haloalkyl group as defined above attachedthrough an oxygen bridge.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, oriodo.

The term “heterocycloalkyl” indicates a saturated monocyclic groupcontaining from 1 to 3 heteroatoms independently chosen from N, O, andS, with remaining ring atoms being carbon or a saturated bicyclic grouphaving at least one ring containing from 1 to 3 heteroatomsindependently chosen from N, O, and S. Monocyclic heterocycloalkylgroups have from 3 to about 8 ring atoms, and more typically have from 5to 7 ring atoms. Some preferred monocyclic heterocycloalkyl groups have5 to 6 ring atoms and 1 or 2 heteroatoms chosen from N, O, and S.Bicyclic heterocycloalkyl groups have 2 saturated rings in fused orspiro orientation, with at least one ring having from 1 to 3 ringheteroatoms. Certain preferred bicyclic heterocycloalkyl groups have a5- or 6-membered nitrogen containing ring in fused or spiro orientationwith a C₃-C₆cycloalkyl group or a 4- to 6-membered heterocycloalkylgroup containing 1 nitrogen atom.

Examples of heterocycloalkyl groups include morpholinyl,thiomorpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl groups. Inthe term “heterocycloalkyl)alkyl” the terms heterocycloalkyl and alkylare as defined above, and the point of attachment is on the alkyl.

Abbreviations

The following chemical abbreviations are used in Schemes 1 and 2 andExamples 1 to 3. Additional abbreviations used in these examples will befamiliar to those of skill in the art of organic chemical synthesis.

m-CPBA meta-Chloroperoxybenzoic acid DIEA N,N-Diisopropylethyl amine DMEDimethyl ether DMF Dimethyl formamide DMSO Dimethylsulfoxide EtOAc EthylAcetate MeOH Methanol PTFE Polytetrafluoroethylene UHP Urea-hydrogenperoxide THF TetrahydrofuranChemical Synthesis

The previously described synthetic route proceeded via synthetic Scheme1 in which the methyl sulfanyl starting material (1) was first oxidizedto a sulfoxide (2) with the use of m-CPBA and then converted to amercapto carboxylate (3) prior to cyclization to form the tricyclic9-H-isothiazolo[5,4-b]quinoline-3,4-dione (4). The9-H-isothiazolo[5,4-b]quinoline-3,4-dione (4) was then substituted atthe 7-position with the appropriate amine to form the final7-substituted-8-alkoxy-9-H-isothiazolo[5,4-b]quinoline-3,4-dione product(5).

Within Scheme 1 the reagents and conditions are as follows: (a) 1 equivm-CPBA, CH₂Cl₂, rt; (b) NaSH.xH₂O, DMF, 50° C.; (c) H₂NOSO₃H, NaHCO₃,THF/water, rt; (d) (S)-1-methyl-1-pyrrolidin-3-yl-ethylamine, DMSO,≧120° C. A significant amount of impurity A (up to ˜35%) is observed inreaction (d) when 8-alkoxy-9H-isothiazolo[5,4-b]quionoline-3,4-diones or8A,9-dihydro-4aH-isothiazolo[5,4-b]quinoline-3,4-diones are preparedusing the method illustrated in Scheme 1. Within Scheme 1, and Scheme 2below, R₆ is hydrogen, halogen, or amino and R₈ is C₁C₆alkyl,C₁-C₂haloalkyl, C₃-C₇cycloalkyl substituted with 0 or 1 or more halogensubstituents. R₇ carries any of the definitions set forth herein forthat variable.

The inventors have discovered a novel synthetic route for preparing7-substituted-8-alkoxy-9-H-isothiazolo[5,4-b]quinoline-3,4-diones and8A,9-dihydro-4aH-isothiazolo[5,4-b]quinoline-3,4-diones. An overview ofthis method is provided in synthetic scheme 2. In this method the methylsulfanyl starting material (1) is oxidized to a sulfone intermediate(6). Within Scheme 2 the reagents and conditions are as follows: (e)excess OXONE (DuPont Specialty Chemicals, active ingredient is potassiumperoxymonosulfate CAS RN 10058-23-8), MeOH/water, 55-60° C.; (f)(R)-1-methyl-1-pyrrolidin-3-yl-ethylamine, DMF, 70° C.; (g) NaSH.xH₂O,DME/water, rt; and (h) H₂NOSO₃H, K₂CO₃, DME/water, rt.

The process illustrated by Scheme 2 presents several advantages over thepreviously used process illustrated by Scheme 1. Preparation of thesulfone intermediate (6) avoids the use of m-CPBA, which is potentiallyexplosive. The process illustrated by Scheme 2 also eliminates the needfor stoichiometric control of the oxidant. OXONE, the oxidant used instep (e) of Scheme 2, may simply be used in excess. The need forchromatographic purification of sulfoxide (2) is eliminated as thesulfone (6) crystallizes easily from the reaction mixture. Impurity B isobserved in reaction (f), but the amount (up to 20%) is less than theamount of impurity A observed in reaction (d). Impurity B is removedeasily by recrystallization from ethyl acetate. In contrast impurity Ain Scheme 1 must be removed using preparative HPLC, a more difficultprocess. Chromatographic purification of the sulfone (6) is notnecessary, however, purification of the sulfoxide (2) is necessary.

Additionally, conversion of (7) to (8) is faster than conversion of (2)to (3) (displacement of the sulfone is more rapid than displacement ofthe sulfoxide). Reaction (f) (conversion of (6) to (7)) employs moreconvenient synthetic conditions than reaction (d) (conversion of (4) to(5)). For example, reaction (f) is conducted at lower temperatures andeliminates use of DMSO (a reactive and high-boiling solvent). Thisreaction produces lower levels of impurities and side products than thereaction of Scheme 1.

The invention provides a process for making anti-microbial compounds ofFormula A and also provides methods for making synthetic intermediatesuseful in the synthesis of compounds of Formula A.

In one aspect the invention includes a method of making a sulfoneintermediate of Formula II comprising oxidizing a compound of Formula Iin which X is fluoro or chloro, preferably fluoro, with an oxidizingagent. This reaction appears in Scheme 2 as reaction (e). In this aspectof the invention the oxidizing agent may be potassium monoperoxysulfate(such as OXONE). Other suitable oxidizing agents include urea hydrogenperoxide (in formic acid) and sodium periodate. Reaction (e) may be runat a temperature of 20° C. to 70° C. Reaction (e) may be run in anaqueous/alcohol (e.g., water/methanol and water/ethanol) solvent systemor may be run in any of the following solvents: acetonitrile,dimethylformamide (DMF), or N-methylpyrrolidone (NMP).

In another aspect the invention includes a method of reacting a sulfonecompound of Formula II with a cyclic secondary amine to form a compoundof Formula III, in which R₇ represents an N-linked heterocycloalkylsubstituent (Reaction (f) in Scheme 2). The product of this step is thenconverted to a thiol compound with a conversion reagent (Reaction (g) inScheme 2).

In some embodiments reaction (f) is performed under dry conditions in apolar solvent. For example, the solvent may be DMF. Other suitablesolvents include dimethylacetamide (DMA), N-methylpyrrolidone (NMP),1,2-dimethoxyethane (DME), and tetrahydrofuran (THF).

The secondary amine (which will become the R₇ substituent) used inreaction (f) may be pyrrolidine, piperidine, piperazine, morpholine,thiomorpholine, or azepane substituted with 0 to 2 substituentsindependently chosen from one or more of (a) and 0 or 1 substituents(b). Wherein (a) is chosen from halogen, hydroxy, amino, nitro,C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy, and (b) isoxo, amino, cyano, hydroxyC₁-C₄allyl, aminoC₁-C₄alkyl, C₁-C₆alkylthio,C₂-C₆alkanoyl, (mono- or di-C₁-C₄alkyl)aminoC₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (C₃-C₇cycloalkyl)aminoC₀-C₄alkyl,(C₃-C₇cycloalkyl)(C₁-C₄alkyl)aminoC₀-C₄alkyl,(heterocycloalkyl)C₀-C₄alkyl, or (aryl)C₀-C₄alkyl, where each of (b)other than oxo and cyano is substituted with 0 to 2 substituentsindependently chosen from halogen, hydroxy, amino, cyano, nitro, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

In some embodiments it is desirable to conduct the reaction in thepresence of an additional amine, such as DIEA.

In some embodiments the secondary amine used in reaction (f) ispyrrolidine, which is substituted with 0 to 2 substituents independentlychosen from one or more of (a) and 0, 1, or 2 substituents (b).

In some embodiments the secondary amine used in reaction (f) ispyrrolidine substituted with (5-membered heteroaryl)C₀-C₄alkyl, which issubstituted with 0 to 2 independently chosen from 0 to 2 substituentsindependently chosen from halogen, hydroxy, amino, cyano, nitro, oxo,—COOH, —CONH₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy,mono- and di-(C₁-C₄alkyl)amino, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.Exemplary 5-membered heteroaryl group includes imidazolyl, thiazolyl,furanyl, oxazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl,or oxadiazolyl group.

In some embodiments the secondary amine is a thiazolylmethyl groupsubstituted with amino or an imidazolyl methyl group substituted withamino, e.g. the secondary amine may be

In some embodiments the secondary amine used in reaction (f) ispyrrolidine substituted with one group (b) and optionally substitutedwith 1 methyl or halogen substituent wherein (b) is oxo, amino, cyano,hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl, C₂-C₄alkanoyl, (mono- ordi-C₁-C₄alkyl)aminoC₀-C₄alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl substitutedwith amino, (C₃-C₇cycloalkylamino)C₀-C₄alkyl, or(C₃-C₇cycloalkyl)(C₁-C₄alkyl)aminoC₀-C₄alkyl.

In some embodiments the secondary amine used in reaction (f) is an amineof the formula

in which R₁₅ is (b); and R₁₆ is 0 or 1 or more substituents chosen fromamino, hydroxy, chloro, fluoro, methyl, methoxy, trifluoromethyl, andtrifluoromethoxy.

In some embodiments the secondary amine used in reaction (f) is

in which R₁₅ is (b); and R₁₆ is 0 or 1 or more substituents chosen fromamino, hydroxy, chloro, fluoro, methyl, methoxy, trifluoromethyl, andtrifluoromethoxy.

R₁₅ may also carry the following definition: oxo, amino, cyano,hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl, C₂-C₄alkanoyl, (mono- ordi-C₁-C₄alkylamino)C₀-C₄alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkyl substitutedwith amino, (C₃-C₇cycloalkylamino)C₀-C₄alkyl, or(C₃-C₇cycloalkyl)(C₁-C₄alkyl)aminoC₀-C₄alkyl. In certain embodiments ofR₁₅ is oxo, cyano, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl, acetyl, (mono- ordi-C₁-C₂alkylamino)C₁-C₄alkyl, cyclopropyl substituted with amino, or(C₃-C₇cycloalkylamino)C₀-C₄alkyl; and R₁₆ is 0 or 1 substituent chosenfrom hydroxy, amino, chloro, and methyl.

In some embodiments the secondary amine used in reaction (f) is1-(pyrrolidin-3-yl)cyclopropanamine; 2-(pyrrolidin-3-yl)propan-2-amine;N-((4-methylpyrrolidin-3-yl)methyl)cyclopropanamine;1-(pyrrolidin-3-yl)ethanamine; N-methyl-1-(pyrrolidin-3-yl)ethanamine;N-methyl-2-(pyrrolidin-3-yl)propan-2-amine;N,N-dimethylpyrrolidin-3-amine; N-methylpyrrolidin-3-amine;N-methyl-1-(pyrrolidin-3-yl)methanamine; pyrrolidin-3-ylmethanamine;4-methylpyrrolidine-3-carbonitrile;N-ethyl-1-(pyrrolidin-3-yl)ethanamine;N-ethyl-2-(pyrrolidin-3-yl)propan-2-amine; pyrrolidin-3-amine;(3-methylpyrrolidin-3-yl)methanol;N,N-dimethyl-1-(pyrrolidin-3-yl)ethanamine;N,N-dimethyl-2-(pyrrolidin-3-yl)propan-2-amine;N,N-dimethyl-1-(pyrrolidin-3-yl)methanamine;N-methyl-1-(pyrrolidin-3-yl)propan-1-amine;N-methyl-1-(pyrrolidin-3-yl)propan-1-amine;N-(1-(pyrrolidin-3-yl)ethyl)cyclopropanamine; orN-(1-(pyrrolidin-3-yl)ethyl)cyclopentanamine.

In some embodiments the secondary amine used in reaction (f) is a 5- or6-membered nitrogen-linked heterocycloalkyl, which has 0 or 1 additionalnitrogen atoms, which 5- or 6-membered nitrogen-linked heterocycloalkylis part of a bicyclic ring system having a fused C₃-C₆cycloalkyl or afused 4- to 6-membered heterocycloalkyl containing 1 nitrogen atom,which bicyclic ring system is substituted with 0, 1, or 2 substituentsindependently chosen from independently chosen from halogen, hydroxy,amino, oxo, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy.

In some embodiments the secondary amine used in reaction (f) is a 5- or6-membered nitrogen-linked heterocycloalkyl which is part of a bicyclicring system is a pyrrolidinyl or piperidinyl and is fused to aC₃-C₆cycloalkyl, pyrrolidinyl, or piperidinyl which bicyclic ring issubstituted with 0, 1, or 2 substituents independently chosen fromhalogen, methyl, and methoxy.

The conversion reagent used in reaction (g) may be NaSH.xH₂O, anhydroussodium hydrosulfite (NaSH.xH₂O where x=0). Other suitable conversionreagents include Na₂S or Na₂S.9H₂O. Reaction (g) may be conducted atroom temperature or at any temperature from 0° C. to 50° C. In certainembodiments reaction (g) is conducted in a polar solvent such as DMF.Other suitable solvents include DME/water, THF/water, EtOH/water. Oxygenshould be excluded from the reaction mixture when conducting reaction(g). Reaction (g) may be conducted in an inert gas atmosphere, forexample under Argon, N₂, or He.

The invention includes a method of cyclization of a compound of FormulaIV to prepare an 8-alkoxy-9H-isothiazolo[5,4-b]quinoline-3,4-dione ofFormula A (reaction (h)).

The cyclization may be effected by reacting a thiol compound of formulaIV with hydroxylamine-O-sulfonic acid. Other suitable reagents foreffecting the cyclization include hydroxylamine compounds such asO-mesitylenesulfonylhydroxylamine and O-nitrophenylhydroxylamine. Thecyclization reaction (h) may be conducted in a polar solvent such asTHF/water. Other suitable solvents include DME/water and DMF/water. Thecyclization reaction (h) can be conducted at basic pH. In certainembodiments the cyclization is conducted at pH 9-10. In certainembodiments the basic pH is supplied by adding K₃PO₄ or NaHCO₃. Othersuitable bases include K₂CO₃ and Et₃N.

Chemical Description

In addition to the definitions set forth in the Summary of Inventionsection for the groups R₅, R₆, R₇, and R₉ these groups may also carryany of the following definitions.

-   The R₂ and R₄ groups

R₂ is C₁-C₆alkyl, or in some embodiments R₂ is C₁-C₄alkyl.

R₄ is C₁-C₆alkyl, or in some embodiments R₄ is C₁-C₄alkyl.

-   The R₅ group

i. R₅ is hydrogen

-   The R₆ group

i. R₆ is fluoro or hydrogen.

ii. R₆ is fluoro.

-   The R₇ group

i. R₇ is a nitrogen-linked heterocycloalkyl group, which has 4 to 8 ringmembers, including 0, 1, or 2 additional ring heteroatoms independentlychosen from N, O, and S, which is substituted with 0 or 1 or moresubstituents independently chosen from (a) and 0, 1, or 2 substituentschosen from (b).

ii. R₇ is a pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, or azepanyl group substituted with with 0 to 2substituents independently chosen from or more of (a) and 0 or 1substituents (b).

iii. R₇ is a pyrrolidinyl group, which is substituted with 0 to 2substituents independently chosen from one or more of (a) and 0 or 1substituents (b).

iv. R₇ is pyrrolidinyl group substituted with one group (b) andoptionally substituted with 1 methyl or halogen substituent wherein (b)is oxo, amino, cyano, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl, C₂-C₄alkanoyl,(mono- or di-C₁-C₄alkyl)aminoC₀-C₄alkyl, (C₃-C₇cycloalkyl)C₀-C₂alkylsubstituted with amino, (C₃-C₇cycloalkylamino)C₀-C₄alkyl, or(C₃-C₇cycloalkyl)(C₁-C₄alkyl)aminoC₀-C₄alkyl; each of which issubstituted with 0 to 2 C₁-C₄alkyl.

v. R₇ is a group of formula

in which R₁₅ is (b); and R₁₆ is 0 or 1 or more substituents chosen fromamino, hydroxy, chloro, fluoro, methyl, methoxy, trifluoromethyl, andtrifluoromethoxy.

vi. In some embodiments R₁₅ is oxo, amino, cyano, hydroxyC₁-C₄alkyl,aminoC₁-C₄alkyl, C₂-C₄alkanoyl, (mono- or di-C₁-C₄alkylamino)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₂alkyl substituted with amino,(C₃-C₇cycloalkylamino)C₀-C₄alkyl, or(C₃-C₇cycloalkyl)(C₁-C₄alkyl)aminoC₀-C₄alkyl.

vii. In certain embodiments R₁₅ is oxo, cyano, hydroxyC₁-C₄alkyl,aminoC₁-C₄alkyl, acetyl, (mono- or di-C₁-C₂alkylamino)C₁-C₄alkyl,cyclopropyl substituted with amino, or (C₃-C₇cycloalkylamino)C₀-C₄alkyl;and R₁₆ is 0 or 1 substituent chosen from hydroxy, amino, chloro, andmethyl.

viii. In other embodiments R₁₅ is hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl,C₂-C₄alkanoyl, (mono- or di-C₁-C₄alkylamino)C₀-C₄alkyl,(C₃-C₇cycloalkyl)C₀-C₂alkyl substituted with amino,(C₃-C₇cycloalkylamino)C₀-C₄alkyl, or(C₃-C₇cycloalkyl)(C₁-C₄alkyl)aminoC₀-C₄alkyl; each of which issubstituted with 0 to 2 C₁-C₄alkyl.

ix. In certain embodiments R₇ is a group of formula

in which R₁₆ is 0 or 1 or more substituents chosen from amino, hydroxy,chloro, fluoro, methyl, methoxy, trifluoromethyl, and trifluoromethoxy;R₂₀ and R₂₁ are independently hydrogen or C₁-C₄alkyl; and R₂₂ and R₂₃are independently hydrogen, C₁-C₄alkyl or R₂₂ and R₂₃ may be joined toform a cyclopropyl or cyclobutyl ring.

x. R₇ is

xii. R₇ is a 5- or 6-membered nitrogen-linked heterocycloalkyl, whichhas 0 or 1 additional nitrogen atoms, which 5- or 6-memberednitrogen-linked heterocycloalkyl is part of a bicyclic ring systemhaving a fused C₃-C₆cycloalkyl or a fused 4- to 6-memberedheterocycloalkyl containing 1 nitrogen atom, which bicyclic ring systemis substituted with 0, 1, or 2 substituents independently chosen fromindependently chosen from halogen, hydroxy, amino, oxo, cyano,C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

xiii. In some embodiments the 5- or 6-membered nitrogen-linkedheterocycloalkyl which is part of a bicyclic ring system is apyrrolidinyl or piperidinyl and is fused to a C₃-C₆cycloalkyl,pyrrolidinyl, or piperidinyl which bicyclic ring is substituted with 0,1, or 2 substituents independently chosen from halogen, methyl, andmethoxy.

xiv. R₇ is a pyrrolidinyl group substituted with (5-memberedheteroaryl)C₀-C₄alkyl, which is substituted with 0 to 3 independentlychosen from 0 to 3 substituents independently chosen from halogen,hydroxy, amino, cyano, nitro, oxo, —COOH, —CONH₂, C₁-C₄alkyl,C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄alkoxy, mono- and di-(C₁-C₄alkyl)amino,C₁-C₂haloalkyl, and C₁-C₂haloalkoxy. The 5-membered heteroaryl group isan imidazolyl, thiazolyl, furanyl, oxazolyl, thienyl, pyrazolyl,triazolyl, tetrazolyl, or oxadiazolyl group in some embodiments.

xv. R₇ is a nitrogen-linked C₁-C₄alkylamino substituted with a 5 or6-membered heteroaryl group having 1 or 2 heteroatoms independentlychosen from N, O, and S, or substituted with a heterocycloalkyl group,which has 4 to 8 ring members, including 1 or 2 ring heteroatomsindependently chosen from N, O, and S; which is substituted with 0 or 1or more substituents independently chosen from (a) and 0, 1, or 2substituents chosen from (b).

xvi. R₇ is C₁-C₄alkylamino substituted with a pyridyl, pyrimidinyl,piperazinyl, piperidinyl, or morpholinyl, each of which is substitutedwith 0, 1, or 2 substituents independently chosen from halogen, hydroxy,amino, oxo, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy.

xvii. R₇ is C₁-C₂alkylamino substituted with pyridyl, piperazinyl,piperidinyl, or morpholinyl, each of which is substituted with 0, 1, or2 substituents independently chosen from halogen, methyl, and methoxy.

xviii. R₇ is a thiazolylmethyl group substituted with amino or animidazolyl methyl group substituted with amino.

xix. R₇ is

xx. R₇ is a nitrogen-linked heterocycloalkyl or heterocycloalkenylgroup, each of which has 4 to 8 ring members, including 0, 1, or 2additional ring heteroatoms independently chosen from N, O, and S,forming part of a bicyclic system with a 3- to 8-membered cycloalkyl orheterocycloalkyl ring in fused or spiro orientation, each of which R₇ issubstituted with 0 or 1 or more substituents independently chosen from(a) and 0 or 1 substituents chosen from (b).

xxi. R₇ is a piperidinyl, piperazinyl, or pyrrolidinyl group, which ispart of a bicyclic system having a spiro attached C₃-C₄cycloalkyl,dioxolanyl, or azetidinyl group, which bicyclic system is substitutedwith 0, 1, or 2 substituents independently chosen from halogen, hydroxy,amino, oxo, cyano, C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy. R₇ is a 5- or 6-membered nitrogen-linkedheterocycloalkyl, which has 0 or 1 additional nitrogen atoms, which 5-or 6-membered nitrogen-linked heterocycloalkyl is part of a bicyclicring system having a fused C₃-C₆cycloalkyl or a fused 4- to 6-memberedheterocycloalkyl containing 1 nitrogen atom, which bicyclic ring systemis substituted with 0, 1, or 2 substituents independently chosen fromindependently chosen from halogen, hydroxy, amino, oxo, cyano,C₁-C₂alkyl, C₁-C₂alkoxy, C₁-C₂haloalkyl, and C₁-C₂haloalkoxy.

xxii. In certain embodiments the 5- or 6-membered nitrogen-linkedheterocycloalkyl which is part of a bicyclic ring system is apyrrolidinyl or piperidinyl and is fused to a C3-C6cycloalkyl,pyrrolidinyl, or piperidinyl which bicyclic ring is substituted with 0,1, or 2 substituents independently chosen from halogen, methyl, andmethoxy.

xxiii. R₇ is a group of the formula

optionally attached to a C₃-C₇ spiro cycloalkyl or a spiroheterocycloalkyl.

xxiv. R₇ is substituted with 0, 1, or 2 substituents independentlychosen from C₁-C₄alkyl, C₁-C₄alkoxy, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl,and C₃-C₇cycloalkyl substituted with amino.

xxv. R₇ is a group of the formula shown in xxiii, substituted with 0, 1,or 2 substituents independently chosen from C₁-C₄alkyl, C₁-C₄alkoxy,hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl, and C₃-C₇cycloalkyl substituted withamino; and R_(A) is hydrogen, C₁-C₂alkyl, or benzyl.

xxvi. R₇ is a group of the formula

-   The R₈ and R₉ groups

i. R₈ is C₁-C₆alkyl.

ii R₈ is C₁-C₄alkyl.

iii. R₈ is difluoromethyl or fluorocyclopropyl.

iv. R₈ is hydrogen.

v. R₉ is C₁-C₄alkyl or cyclopropyl, or R₉ is phenyl substituted with 2substituents chosen from halogen, hydroxy, amino, C₁-C₂alkyl,C₁-C₂alkoxy, mono- and di-(C₁-C₂)alkylamino, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy.

vi. R₉ is cyclopropyl.

vii. Any of the above definitions for the variables R₅ to R₇ and R₉ maybe combined to form an intermediate of Formula I to IV so long as auseful intermediate results. A useful intermediate is an intermediatethat is sufficiently stable to be used in one of reactions (e) to (h)shown in Scheme 2.

EXAMPLES

General Methods

All nonaqueous reactions are performed under an atmosphere of dry argongas (99.99%). NMR spectra are recorded at ambient temperature using aBruker Avance 300 spectrometer (¹H at 300.1 MHz and ¹³C at 75.5 MHz,).The chemical shifts for ¹H and ¹³C are reported in parts per million (δ)relative to external tetramethylsilane and are referenced to signals ofresidual protons in the deuterated solvent. Analytical HPLC is performedusing a Waters X-bridge C18 150×4.6 mm 3.5 μm column with a 20-minlinear gradient elution of increasing concentrations of acetonitrile inwater (5 to 95%) containing 0.1% trifluoroacetic acid with a flow rateof 1.0 mL/min and WV detection at 254 nm. Low-resolution mass spectraare recorded on a Thermo Finnigan Surveyor MSQ instrument (operating inAPCI mode) equipped with a Gilson liquid chromatograph. Unless notedotherwise, the quasi-molecular ions, [M+H]⁺, observed in thelow-resolution mass spectra are the base peaks. Melting points arerecorded on an Electrothermal Model IA9100 digital melting pointapparatus.

The skilled artisan will readily appreciate that certain reactions arebest carried out when other functionalities are masked or protected inthe compound, thus increasing the yield of the reaction and/or avoidingany undesirable side reactions. Often, the skilled artisan utilizesprotecting groups to accomplish such increased yields or to avoid theundesired reactions. These reactions are found in the literature and arealso well within the scope of the skilled artisan.

This invention is further illustrated by the following examples thatshould not be construed as limiting. The contents of all references,patents and published patent applications cited throughout thisapplication are incorporated herein by reference.

Example 1 SYNTHESIS OF(R)-7-[3-(1-AMINO-1-METHYLETHYL)PYRROLIDIN-1-YL]-9-CYCLOPROPYL-6-FLUORO-8-METHOXY-9H-ISOTHIAZOLO[5,4-B]QUNIOLINE-3,4-DIONE(5) Step 1. Ethyl1-cyclopropyl-6,7-difluoro-2-methanesulfonyl-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate(6)

Water (180 mL), followed by Oxone® (Dupont Specialty Chemicals) (170 g,277 mmol), is added to a suspension of 1 in MeOH (510 mL). The reactionmixture is heated with stirring at 55-60° C. for 3 h. The reactionmixture is cooled to room temperature, diluted with water (40 mL), andstirred at 5° C. (ice bath) for 30 min. The resulting crystals arecollected by filtration, washed with water (2×100 mL), and dried toafford 6 (13.8 g). This material was used in the next step withoutfurther purification. mp 177-178° C. ¹H NMR (DMF-d₇): δ0.62 (m, 1H),1.11 (m, 2H), 1.29 (m, 1H), 1.32 (t, J_(H—H)=7.0 Hz, 3H), 3.76 (s, 3H),4.18 (m, 1H), 4.21 (d, J_(H—F)=2.0 Hz, 3H), 4.33 (q, J_(H—H)=7.0 Hz,2H), 7.64 (dd, J_(H—F)=10.0 Hz, 8.5 Hz, 1H).

Step 2(R)-7-[3-(1-amino-1-methyl-ethyl)-pyrrolidine-yl]-1-cyclopropyl-6-fluoro-2-methanesulfonyl-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid Ethyl Ester (7)

A mixture containing compound (6) (3.88 g, 9.67 mmol), compound 10 (1.64g, 12.8 mmol), anhydrous DIEA (5.05 g, 39.1 mmol, dried over 4 Åsieves), and anhydrous DMF (40 mL) is heated at 70° C. under anatmosphere of argon gas. After heating for 4.5 h (LC-MS analysis shows˜7% compound (6) remained), the reaction mixture is cooled to roomtemperature, diluted with EtOAc (200 mL), and washed with water (100mL). The aqueous layer is extracted with EtOAc (100 mL), and thecombined organic layers are washed with a saturated aqueous solution ofsodium bicarbonate (100 mL). The organic layer is diluted with water(100 mL) and treated with an aqueous solution of HCl (4 N) until theaqueous layer is acidic (pH 2-3 after shaking the mixture vigorously).The organic layer is separated, and this process is repeated. Thecombined aqueous layers are diluted with EtOAc (100 mL) and treated withan aqueous solution of sodium hydroxide (6 N) until the aqueous layer isbasic (pH ˜8 after shaking the mixture vigorously). The aqueous layer isseparated, and this process is repeated. The combined organic layers aredried over magnesium sulfate, filtered, and concentrated under reducedpressure giving an orange solid (3.27 g of an ˜80:20 mixture of compound(7) and impurity B). This solid is recrystallized from hot EtOAc (˜60mL) furnishing 2.18 g (44% yield) of pure compound 7 as a bright yellowsolid. LC-MS m/z calcd for C₂₄H₃₂FN₃O₆S 509 ([M⁺]); found 510 ([M+H]⁺).

This reaction should not be allowed to proceed for more than a few hours(not overnight) as prolonged reaction time can lead to the formation ofmore side products. The product should be ˜95% pure (based on HPLC),with only a trace amount of impurity B.

Step 3.(R)-7-[3-(1-amino-1-methyl-ethyl)-pyrrolidin-yl]-1-cyclopropyl-6-fluoro-2-mercapto-8-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid Ethyl Ester (8)

Compound 7 (1.04 g, 2.04 mmol) is partially dissolved in DME (40 mL)under an atmosphere of argon. Sodium hydrosulfide hydrate (Aldrich,72.6% by titration, 465 mg, 6.02 mmol) in water (3.0 mL) is added tothis solution. The resulting mixture is sparged slowly with argon for 30min. The progress of the reaction is monitored by HPLC-MS, and judged tobe complete (≦2% of 7 remains) after 11.5 h. Excess sodium hydrosulfideis quenched upon addition of aq HCl (4.5 mL, 4 N). The resulting orangesolution (pH ˜2) is sparged with argon (30 min) to remove the generatedhydrogen sulfide.

Step. 4(R)-7-[3-(1-amino-1-methyl-ethyl)-pyrrolidin-1-yl]-9-cyclopropyl-6-fluoro-8-methoxy-9H-isothiazolo[5,4-b]-quinoline-3,4-dione(5)

A solution of potassium carbonate (4.26 g, 30.8 mmol) in water (25 mL)is next added to this solution to give a clear yellow solution (pH9-10). The clear yellow solution is then sparged with argon for ˜5 min.Finally, hydroxylamine-O-sulfonic acid (0.93 g, 8.2 mmol) is addedportionwise as a solid, with immediate evolution of gas and formation ofthe product as a yellow precipitate. After stirring for 16 h, thereaction mixture (pH 10.2) is acidified with aq HCl to pH 8.3 (theapproximate isoelectric point of 5) causing additional product toprecipitate from solution. The reaction mixture is concentrated underreduced pressure (final volume ˜40 mL). The yellow precipitate iscollected by centrifugation, washed with water (3×40 mL, withsonication), and lyophilized to give 0.80 g of 5.

Example 2 SYNTHESIS OF(R)-7-[3-(2-AMINOPROPAN-2-YL)PYRROLIDIN-1-YL]-9-CYCLOPROPYL-8-(DIFLUOROMETHOXY)-6-FLUOROUISOTHIAZOLO[5,4-B]QUINOLINE3,(2H,9H)-DIONE(11) Step 1. Ethyl1-cyclopropyl-8-(difluoromethoxy)-6,7-difluoro-2-methanesulfonyl-4-oxo-1,4-dihydro-quinoline-3-carboxylate(12)

Water (510 mL), followed by OXONE (Dupont Specialty Chemicals) (170 g,277 mmol), is added to a suspension of 13 (23 g) in EtOH (510 mL). Thereaction mixture is heated with stirring at 55-60° C. overnight. Thereaction mixture is cooled to room temperature, EtOH is removed underreduced pressure, diluted with water (40 mL), and extracted with EtOAc.The organic layer is dried (Na₂SO₄), concentrated and purified to get(40% EtOAc in Hexanes) 13.8 g of sulfone 2 as white solid. ¹H-NMR(CDCl₃): δ 0.39-0.46 (1H, m), 0.85-0.93 (1H, m), 1.09-1.14 (1H, m),1.24-1.29 (1H, m), 1.38 (3H, t, J=6.0 Hz), 3.47 (3H, s), 4.12-4.19 (1H,m), 4.37-4.48 (2H, m), 6.66 (1H, td, J=72 Hz, 0.9 Hz), 7.91 (1H, dd,J=12 Hz, 9 Hz); ¹⁹F: δ −137.9 (1F, d, J=22.5 Hz), −134.1 (1F, d, J=19.7Hz), −82.1 (2F, d, J=8.5 Hz); LRMS calc. for C₁₇H₁₅F₄NO₆S 437, found 438(M+1).

Step 2.(R)-7-[3-(1-amino-1-methyl-ethyl)-pyrrolidin-yl]-1-cyclopropyl-6-fluoro-2-methanesulfonyl-8(difluor-methoxy)-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid Ethyl Ester (14)

A mixture containing compound (12) (3.0 g, 6.86 mmol), compound (10)(1.32 g, 10.3 mmol), anhydrous DIEA (6.03 ml, 34.3 mmol, dried over 4 Åsieves), and anhydrous N,N-dimethyl acetamide (DMA) (40 mL) is heated at80° C. under an atmosphere of argon gas. After heating for 1 h, thereaction mixture is cooled to room temperature, diluted with EtOAc (200mL), and washed with water (100 mL). The aqueous layer is extracted withEtOAc (100 mL), and the combined organic layers are washed with asaturated aqueous solution of sodium bicarbonate (100 mL). The organiclayer is diluted with water (100 mL) and treated with an aqueoussolution of HCl (4 N) until the aqueous layer is acidic (pH 2-3 aftershaking the mixture vigorously). The organic layer is separated, andthis process is repeated. The combined aqueous layers are diluted withEtOAc (100 mL) and treated with an aqueous solution of sodium hydroxide(6 N) until the aqueous layer is basic (pH ˜8 after shaking the mixturevigorously). The aqueous layer is separated, and this process isrepeated. The combined organic layers are dried over magnesium sulfate,filtered, and concentrated under reduced pressure giving an orange solid(4.8 g). ¹H-NMR (CDCl₃): δ 0.36-0.41 (1H, m), 0.83-0.88 (1H, m),0.98-1.03 (1H, m), 1.19 (6H, d, J=1.8 Hz), 1.18-1.26 (1H, m), 1.38 (3H,t, J=6.0 Hz), 1.71-1.78 (1H, m), 1.98-2.03 (1H, m), 2.22-2.34 (1H, m),3.36-3.50 (2H, m), 3.43 (3H, s), 3.82-3.91 (1H, m), 4.02-4.13 (2H, m),4.36-4.47 (2H, m), 6.19 (1H, t, J=75 Hz), 7.62 (1H, d, J=13.8 Hz); ¹⁹F:δ −121.3, −82.9 (d, J=39.5 Hz); LRMS calc. for C₂₄H₃₀F₃N₃O₆S 545, found546 (M+1).

Step 3.(R)-7-[3-(1-amino-1-methyl-ethyl)-pyrrolidin-yl]-1-cyclopropyl-6-fluoro-2-mercapto-8(difluoro-methoxy)-4-oxo-1,4-dihydro-quinoline-3-carboxylicAcid Ethyl Ester (15)

Compound 14 (1.6 g, 2.93 mmol) is dissolved in DMF (40 mL) under anatmosphere of argon. Sodium hydrosulfide hydrate crystals (Aldrich,72.6% by titration, 330 mg, 5.88 mmol) are added to this solution. Theresulting mixture is sparged slowly with argon for 30 min. The progressof the reaction is monitored by HPLC-MS, and judged to be complete (≦2%of 14 remains) after 5 h. Excess sodium hydrosulfide is quenched uponaddition of aq. HCl (4.5 mL, 4 N). The resulting orange solution (pH ˜2)is sparged with argon (30 min) to remove the generated hydrogen sulfide.DMF is removed under reduced pressure to give orange oil.

Step. 4(R)-7-[3-(1-amino-1-methyl-ethyl)-pyrrolidin-1-yl]-9-cyclopropyl-6-fluoro-8-(difluoromethoxy)-9H-isothiazolo[5,4-b]-quinoline-3,4-dione(16)

The above oil is taken in THF (30 ml) and 30 ml of water. Solid sodiumbicarbonate is added till the pH is 9-10. This heterogeneous solution isthen sparged with argon for -5 min. Finally, hydroxylamine-O-sulfonicacid (1.33 g, 11.7 mmol) is added portion-wise as a solid, withimmediate evolution of gas and formation of the product as a yellowprecipitate. After stirring for 16 h, the reaction mixture isconcentrated to remove THF. Orange solid separates. The reaction mixturewas centrifuged and the supernatant is decanted. The product along withsolid sodium bicarbonate is washed with water (3×40 mL, withsonication), and lyophilized to give 0.75 g of 16. ¹H-NMR (TFA-D): δ1.19-1.33 (2H, m), 1.45-1.57 (2H, m), 1.58 (6H, s), 1.95-2.05 (1H, m),2.27-2.36 (1H, m), 2.78-2.88 (1H, m), 3.81-4.23 (5H, m), 6.41 (1H, t,J=72 Hz), 7.98 (1H, d, J=12.9 Hz); ¹⁹F (DMSO-D₆): δ −124.9, -84.4 (d,J=42.3 Hz); LRMS calc. for C₂₁H₂₃F₃N₄O₃S 468, found 469 (M+1).

Example 3 SYNTHESIS OF7-((R)-3-((S)-1-AMINOETHYL)PYRROLIDIN-1-YL)-9-CYCLOPROPYL-6-FLUORO-8-METHOXYISOTHIAZOLO[5,4-B]QUINOLINE-3,4(2H,9H)-DIONE(17) Step 1. Ethyl7-((R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-8-methoxy-2-(methylsulfonyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate(18)

A mixture containing compound (6) (16.7 g, 41.6 mmol), compound (10)(5.58 g, 48.9 mmol), anhydrous DIEA (20.8 g, 161 mmol, dried over 4 Åsieves), and anhydrous DMF (128 mL) is heated at 70° C. under anatmosphere of argon gas. After heating for 6 h (LC-MS analysis shows ˜7%compound (6) remained), the reaction mixture is cooled to roomtemperature, diluted with EtOAc (500 mL), and washed with water (500mL). The aqueous layer is extracted with EtOAc (500 mL), and thecombined organic layers are washed with a saturated aqueous solution ofsodium bicarbonate (500 mL). The organic layer is diluted with water(500 mL) and treated with an aqueous solution of HCl (4 N) until theaqueous layer is acidic (pH 2-3 after shaking the mixture vigorously).The organic layer is separated, and this process is repeated. Thecombined aqueous layers are diluted with EtOAc (500 mL) and treated withan aqueous solution of sodium hydroxide (6 N) until the aqueous layer isbasic (pH ˜8 after shaking the mixture vigorously). The aqueous layer isseparated, and this process is repeated. The combined organic layers aredried over magnesium sulfate, filtered, and concentrated under reducedpressure giving an orange solid. Crude solid is used directly to nextreaction.

Step 2. Ethyl7-((R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro-2-mercapto-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate(19)

Compound 18 from previous reaction is partially dissolved in DME (150mL) under an atmosphere of argon. Sodium hydrosulfide hydrate (Aldrich,72.6% by titration, 4.65 g, 60.2 mmol) in water (15.0 mL) is added tothis solution. The resulting mixture is sparged slowly with argon for 30min. The progress of the reaction is monitored by HPLC-MS, and judged tobe complete (≦2% of 18 remains) after 15 h. Excess sodium hydrosulfideis quenched upon addition of aq HCl (30 mL, 6 N). The resulting orangesolution (pH ˜2) is sparged with argon (3 h) to remove the generatedhydrogen sulfide.

Step 3.7-((R)-3-((S)-1-aminoethyl)pyrrolidin-1-yl)-9-cyclopropyl-6-fluoro-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione(19)

A solution of potassium carbonate (30 g, 217 mmol) in water (150 mL) isnext added to this solution to give a clear yellow solution (pH 9-10).The clear yellow solution is then sparged with argon for 5 min. Finally,hydroxylamine-O-sulfonic acid (93 g, 82 mmol) is added portionwise as asolid, with immediate evolution of gas and formation of the product as ayellow precipitate. After stirring for 15 h, the reaction mixture (pH10.2) is acidified with aq HCl to pH 8.3 (the approximate isoelectricpoint of 20) causing additional product to precipitate from solution.The reaction mixture is concentrated under reduced pressure (finalvolume 40 mL). The yellow precipitate is collected by centrifugation,washed with water (3×40 mL, with sonication), and lyophilized to give7.3 g of 20. LC-MS m/z calcd for C₂₀H₂₃FN₄O₃S 418 ([M+]); found 419([M+H]+). ¹H NMR (DMSO-d₆) δ 8.15 (br, 3H), 7.55 (d, J_(H,F)=13.9 Hz1H), 3.86-3.51 (m, 3H), 3.52 (s, 3H, methoxy), 3.51-3.45 (m, 2H), 3.29(m, 1H), 2.42 (m, 1H), 2.09 (m, 1H), 1.75 (m, 1H), 1.29 (d, J=6.5 Hz,3H, methyl), 1.14 (m, 2H, c-Pr), 0.95 (m, 2H, c-Pr). ¹⁹F NMR (DMSO-d₆) δ−125.4 (s, 1F).

1. A compound of the formula:

wherein R₂ is C₁-C₆alkyl, C₂-C₆alkenyl, (C₃-C₇cycloalkyl)C₀-C₄alkyl,(aryl)C₀-C₄alkyl, or (C₂-C₆heterocycloalkyl)C₀-C₂alkyl, each of which issubstituted with 0 to 5 substituents independently chosen from halogen,hydroxy, amino, cyano, nitro, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl,C₁-C₂haloalkoxy, mono- and di-C₁-C₄alkylamino, C₂-C₄alkanoyl, andC₁-C₄alkylthio; R₄ is C₁-C₆alkyl, C₂-C₆alkenyl,(C₃-C₇cycloalkyl)C₀-C₄alkyl, (aryl)C₀-C₄alkyl, or(C₂-C₆heterocycloalkyl)C₀-C₂alkyl, each of which is substituted with 0to 5 substituents independently chosen from halogen, hydroxy, amino,cyano, nitro, C₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₂haloalkyl, C₁-C₂haloalkoxy,mono- and di-C₁-C₄alkylamino, C₂-C₄alkanoyl, and C₁-C₄alkylthio; R₅ ishydrogen, hydroxy, amino, C₁-C₂alkyl, C₁-C₂alkoxy, mono- ordi-(C₁-C₄alkyl)amino, or mono- or di-C₁-C₄alkylhydrazinyl; R₆ ishydrogen, halogen, or amino; X is chloro, bromo, fluoro; iodo, ortriflate; R₈ is C₁-C₆alkyl, C₁-C₂haloalkyl, or C₃-C₇cycloalkylsubstituted with 0 or 1 or more halogen atoms; and R₉ is C₁-C₄alkyl,cyclopropyl, or phenyl, each of which is substituted with 0 to 3substituents independently chosen from halogen, hydroxy, amino,C₁-C₂alkyl, C₁-C₂alkoxy, mono- and di-(C₁-C₂)alkylamino, C₁-C₂haloalkyl,and C₁-C₂haloalkoxy.
 2. A compound of claim 1, wherein R₂ is C₁-C₄alkyl.3. A compound of claim 1, wherein R₂ is ethyl.
 4. A compound of claim 1,wherein R₄ is C₁-C₄alkyl.
 5. A compound of claim 4, wherein R₄ ismethyl.
 6. A compound of claim 1, wherein R₂ is ethyl and R₄ is methyl.7. A compound of claim 1, wherein R₅ is hydrogen.
 8. A compound of claim1, wherein R₆ is fluoro or hydrogen.
 9. A compound of claim 8, whereinR₆ is fluoro.
 10. A compound of claim 1, wherein R₈ is methoxy; and R₉is C₁-C₄alkyl or cyclopropyl, or R₉ is phenyl substituted with 2substituents chosen from halogen, hydroxy, amino, C₁-C₂alkyl,C₁-C₂alkoxy, mono- and di-(C₁-C₂)alkylamino, C₁-C₂haloalkyl, andC₁-C₂haloalkoxy.
 11. A compound of claim 10, wherein R₉ is cyclopropyl.12. A process for the preparation of a compound of claim 1, comprisingoxidizing a compound of the formula

with an oxidizing agent to produce a compound of claim
 1. 13. Theprocess of claim 12, wherein the oxidizing agent is potassiummonoperoxysulfate, urea hydrogen peroxide, meta-chloroperbenzoic acid,UHP, sodium periodate, or a mixture of any of the foregoing.